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Isolation of Human Atrial Myocytes for Simultaneous Measurements of Ca2+ Transients and Membrane Currents
Published on: July 3, 2013
Ca(2+) cycling properties are conserved despite bradycardic effects of heart failure in sinoatrial node cells
Arie O Verkerk1, Marcel M G J van Borren2, Antoni C G van Ginneken1
1Department of Anatomy, Embryology and Physiology, Academic Medical Center, University of Amsterdam Amsterdam, Netherlands.
Insights
Heart failure (HF) in sinoatrial node (SAN) cells slows intracellular calcium ([Ca2+]i) transient decay, impacting pacemaker activity. Reduced [Ca2+]i rise during beta-adrenergic stimulation may impair heart rate regulation in HF.
Area of Science:
- Cardiology
- Cell Physiology
- Biophysics
Background:
- Heart failure (HF) in animal models is associated with decreased heart rate, linked to sinoatrial node (SAN) intrinsic cycle length.
- SAN cell pacemaker activity involves complex interactions between the membrane clock and the intracellular calcium ([Ca2+]i) clock.
- HF-induced remodeling of the membrane clock in SAN cells may affect [Ca2+]i homeostasis, an area requiring further investigation.
Purpose of the Study:
- To investigate the effects of heart failure (HF) on intracellular calcium ([Ca2+]i) homeostasis in sinoatrial node (SAN) cells.
- To analyze the impact of HF on [Ca2+]i transient dynamics and their relationship with pacemaker activity.
- To explore the consequences of altered [Ca2+]i handling on SAN cell function during autonomic stimulation.
Main Methods:
- Isolation of SAN cells from control and HF rabbit models.
- Measurement of intracellular calcium ([Ca2+]i) concentrations using indo-1 fluorescence.
- Simultaneous recordings of action potentials (APs) and Na+-Ca2+ exchange current (INCX) using patch-clamp techniques.
Main Results:
- HF SAN cells exhibited significantly lower spontaneous [Ca2+]i transient frequency, indicating prolonged intrinsic cycle length.
- A slower [Ca2+]i transient decay was observed in HF SAN cells, potentially due to reduced sarcoplasmic reticulum Ca2+ uptake.
- No significant changes were found in other [Ca2+]i transient parameters, sarcoplasmic reticulum Ca2+ content, INCX density, or the INCX-[Ca2+]i relationship.
- While slower [Ca2+]i decay might increase INCX during diastolic depolarization, this is likely counteracted by increased intracellular Na+ in HF.
- Late diastolic [Ca2+]i rise during beta-adrenergic stimulation was reduced in HF SAN cells.
Conclusions:
- HF SAN cells display a slower [Ca2+]i transient decay with minimal direct impact on overall pacemaker activity.
- The reduced late diastolic [Ca2+]i rise under beta-adrenergic stimulation in HF may contribute to an impaired ability to increase intrinsic heart rate.
- These findings highlight alterations in [Ca2+]i handling as a potential mechanism underlying bradycardia in heart failure.
Background:
In animal models of heart failure (HF), heart rate decreases due to an increase in intrinsic cycle length (CL) of the sinoatrial node (SAN). Pacemaker activity of SAN cells is complex and modulated by the membrane clock, i.e., the ensemble of voltage gated ion channels and electrogenic pumps and exchangers, and the Ca(2+) clock, i.e., the ensemble of intracellular Ca(2+) ([Ca(2+)]i) dependent processes. HF in SAN cells results in remodeling of the membrane clock, but few studies have examined its effects on [Ca(2+)]i homeostasis.
Methods:
SAN cells were isolated from control rabbits and rabbits with volume and pressure overload-induced HF. [Ca(2+)]i concentrations, and action potentials (APs) and Na(+)-Ca(2+) exchange current (INCX) were measured using indo-1 and patch-clamp methodology, respectively.
Results:
The frequency of spontaneous [Ca(2+)]i transients was significantly lower in HF SAN cells (3.0 ± 0.1 (n = 40) vs. 3.4 ± 0.1 Hz (n = 45); mean ± SEM), indicating that intrinsic CL was prolonged. HF slowed the [Ca(2+)]i transient decay, which could be explained by the slower frequency and reduced sarcoplasmic reticulum (SR) dependent rate of Ca(2+) uptake. Other [Ca(2+)]i transient parameters, SR Ca(2+) content, INCX density, and INCX-[Ca(2+)]i relationship were all unaffected by HF. Combined AP and [Ca(2+)]i recordings demonstrated that the slower [Ca(2+)]i transient decay in HF SAN cells may result in increased INCX during the diastolic depolarization, but that this effect is likely counteracted by the HF-induced increase in intracellular Na(+). β-adrenergic and muscarinic stimulation were not changed in HF SAN cells, except that late diastolic [Ca(2+)]i rise, a prominent feature of the Ca(2+) clock, is lower during β-adrenergic stimulation.
Conclusions:
HF SAN cells have a slower [Ca(2+)]i transient decay with limited effects on pacemaker activity. Reduced late diastolic [Ca(2+)]i rise during β-adrenergic stimulation may contribute to an impaired increase in intrinsic frequency in HF SAN cells.
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